The AI-based small molecule drug discovery has become a significant trend at the intersection of computer science and life sciences. In the pursuit of novel compounds, fragment-based drug discovery has emerged as a novel approach. The Generative Pre-trained Transformers (GPT) model has showcased remarkable prowess across various domains, rooted in its pre-training and representation learning of fundamental linguistic units. Analogous to natural language, molecular encoding, as a form of chemical language, necessitates fragmentation aligned with specific chemical logic for accurate molecular encoding. This review provides a comprehensive overview of the current state of the art in molecular fragmentation. We systematically summarize the approaches and applications of various molecular fragmentation techniques, with special emphasis on the characteristics and scope of applicability of each technique, and discuss their applications. We also provide an outlook on the current development trends of molecular fragmentation techniques, including some potential research directions and challenges.

Sentiment analysis based on social media text is found to be essential for multiple applications such as project design, measuring customer satisfaction, and monitoring brand reputation. Deep learning models that automatically learn semantic and syntactic information have recently proved effective in sentiment analysis. Despite earlier studies’ good performance, these methods lack syntactic information to guide feature development for contextual semantic linkages in social media text. In this paper, we introduce an enhanced LSTM-based on dependency parsing and a graph convolutional network (DPG-LSTM) for sentiment analysis. Our research aims to investigate the importance of syntactic information in the task of social media emotional processing. To fully utilize the semantic information of social media, we adopt a hybrid attention mechanism that combines dependency parsing to capture semantic contextual information. The hybrid attention mechanism redistributes higher attention scores to words with higher dependencies generated by dependency parsing. To validate the performance of the DPG-LSTM from different perspectives, experiments have been conducted on three tweet sentiment classification datasets, sentiment140, airline reviews, and self-driving car reviews with 1,604,510 tweets. The experimental results show that the proposed DPG-LSTM model outperforms the state-of-the-art model by 2.1% recall scores, 1.4% precision scores, and 1.8% F1 scores on sentiment140.

Existing formats based on the simplified molecular input line entry system (SMILES) encoding and molecular graph structure are designed to encode the complete semantic and structural information of molecules. However, the physicochemical properties of molecules are complex, and a single encoding of molecular features from SMILES sequences or molecular graph structures cannot adequately represent molecular information. Aiming to address this problem, this study proposes a sequence graph cross-attention (SG-ATT) representation architecture for a molecular property prediction model to efficiently use domain knowledge to enhance molecular graph feature encoding and combine the features of molecular SMILES sequences. The SG-ATT fuses the two-dimensional molecular features so that the current model input molecular information contains molecular structure information and semantic information. The SG-ATT was tested on nine molecular property prediction tasks. Among them, the biggest SG-ATT model performance improvement was 4.5% on the BACE dataset, and the average model performance improvement was 1.83% on the full dataset. Additionally, specific model interpretability studies were conducted to showcase the performance of the SG-ATT model on different datasets. In-depth analysis was provided through case studies of in vitro validation. Finally, network tools for molecular property prediction were developed for the use of researchers.

The imperfect modeling of ternary complexes has limited the application of computer-aided drug discovery tools in PROTAC research and development. In this study, a language model for PROTAC molecule design pipeline named LM-PROTAC was developed, which stands for language model-driven Proteolysis Targeting Chimera, by embedding a transformer-based generative model with dual constraints on structure and properties. This study started with the idea of segmentation and representation of molecules and protein. Firstly, a language model-driven affinity model for protein compounds to screen molecular fragments with high affinity for the target protein. Secondly, structural and physicochemical properties of these fragments were constrained during the generation process to meet specific scenario requirements. Finally, a two-round screening was performed on the preliminary generated molecules using a multidimensional property prediction model. This process identified a batch of PROTAC molecules capable of degrading disease-relevant target proteins. These molecules were subsequently validated through in vitro experiments, thus providing a complete solution for language model-driven PROTAC drug generation. Taking Wnt3a, a key tumor-related target, as a POI of degradation, the LM-PROTAC pipeline successfully generated effective PROTAC molecules. The molecular distribution experiments demonstrated the high similarity of the generated molecules to the original dataset, validating the generative model’s effectiveness in accurately defining chemical space. Molecular dynamics simulations confirmed the stable interactions between the PROTAC molecules and target proteins, while protein degradation experiments verified the efficacy of the generated PROTAC molecules in degrading target proteins. The entire LM-PROTAC pipeline is reusable and can generate degraders for other target proteins within 50 days, significantly improving the efficiency of drug discovery for undruggable targets.